Human mesenchymal stem cells (MSCs) are the precursor cells that form and heal nearly all of the[unreadable] mechanical tissues in the human body. MSCs are now being isolated from adults to understand the[unreadable] fundamental biology of how these cells are regulated as a population, and to explore whether these cells can[unreadable] be differentiated and re-implanted as a cellular therapy in order to arrest or even reverse degeneration and[unreadable] damage to specific tissues. In several disease processes such as osteoporosis, a major cause of[unreadable] progressive tissue degeneration and damage may involve a shift in lineage specification of the MSCs leading[unreadable] to an inadequate supply of healthy MSCs and their daughter cells. The long term objective of this research[unreadable] is to characterize the role of adhesive and soluble cues, and the downstream signaling pathways, that drive[unreadable] the lineage specification and differentiation of human mesenchymal stem cells, in order to identify novel[unreadable] mechanisms to treat these degenerative diseases.[unreadable] The mesenchymal stem cell (MSC) is a multipotent cell capable of differentiating into distinct[unreadable] connective tissue lineages depending on cues present in the surrounding tissue microenvironment. While[unreadable] much effort has focused on identifying soluble differentiation factors such as the bone morphogenic proteins[unreadable] (BMPs), little is known about the role of cell adhesion to extracellular matrix (ECM) in determining MSC fate.[unreadable] Understanding these cues may provide better handles to specifically direct stem cell fate in many settings[unreadable] involving stem cell therapy. We have recently discovered that integrin-mediated adhesion of MSCs triggers[unreadable] changes in cell morphology and RhoA activity, which in turn modulate a commitment switch in MSCs[unreadable] between adipogenic and osteogenic lineages. The working hypothesis underlying the present proposal is[unreadable] that cell adhesion cooperates with signals from soluble cues to regulate the commitment and differentiation[unreadable] of human mesenchymal stem cells, and that this cooperative signaling involves RhoA.[unreadable] The goal of this 2-year Pilot and Feasibility proposal therefore is to obtain additional preliminary data[unreadable] in three key studies in order to elaborate our working hypothesis, and then to pursue support for this[unreadable] research by the R01 mechanism. The specific aims are: 1. To investigate the cooperative role of BMP[unreadable] signaling and cell adhesion in MSC gene expression; 2. To investigate the cooperation between BMP[unreadable] signaling and cell adhesion in regulating RhoA activity; and 3. To investigate the effects of BMP and RhoA[unreadable] signaling on MSC commitment in an animal model.